Scientists at Johns Hopkins University have identified how vitamin A derivatives and thyroid hormones help shape the human fovea, the retinal region responsible for sharp central vision. Their findings suggest that some blue-light-sensitive cone cells present early in fetal development may later transform into red- and green-light-sensitive cells, challenging a model that has influenced vision research for nearly 30 years.
Recreating the developing human retina
The research, published in Proceedings of the National Academy of Sciences, could change scientists’ understanding of how the human eye develops. It may also inform future research into treatments for macular degeneration, glaucoma and other diseases that cause vision loss.
“This is an important step toward understanding the inner workings of the central retina, a critical part of the eye and the first to fail in people with macular degeneration,” said Robert J. Johnston Jr., an associate professor of biology at Johns Hopkins University who led the study. “By understanding this region better and developing organoids that mimic its function, we hope to one day grow and transplant these tissues to restore vision.”
To study how human vision forms, Johnston and his colleagues used miniature versions of human retinal tissue known as organoids. The team helped develop the experimental techniques used to grow these structures over the past few years.
The organoids are small clusters of cells grown from fetal cells that reproduce important features of developing human tissue. By observing them for several months, the researchers could track changes that would be extremely difficult to study during pregnancy.
Their work focused on the fovea, a small region at the center of the retina. The retina is the light-sensitive layer at the back of the eye that converts incoming light into signals the brain can interpret. The fovea is specialized for detailed central vision, allowing people to read, recognize faces and distinguish fine details.
Although it occupies only a small part of the retina, the fovea is responsible for about 50% of human visual perception, according to the researchers.
The cellular basis of sharp central vision
A key to understanding the fovea is a group of specialized light-detecting cells called cones. Rod cells are particularly important for vision in dim light, while cones support daytime vision and color perception.
Humans have three types of cones, each most sensitive to a different range of wavelengths. They are commonly described as blue, green and red cones. By comparing signals from these cells, the brain can distinguish a remarkably broad range of colors.
Cones are not distributed evenly across the retina. The fovea contains red and green cones but lacks the blue cones found in other retinal regions. This arrangement is essential to the eye’s clear central vision.
Scientists have struggled for decades to explain how this pattern develops. Commonly studied animals such as mice and fish do not have the same retinal tissue found in humans, making them poor models for investigating the development of these specialized cells.
Human retinal organoids have provided a new way to investigate the long-standing question.
Vitamin A signaling and thyroid hormones guide cone development
The researchers found evidence that foveal cone placement results from two coordinated processes. Together, these processes help determine which cell types form in the central retina and how some cells change as development progresses.
Between 10 and 12 weeks of fetal development, a small number of blue cones initially appear in the fovea. By week 14, however, these cells appear to have transformed into red and green cones.
The team identified two chemical influences involved in this process.
The first is retinoic acid, a molecule produced from vitamin A. Retinoic acid helps control cell development and specialization throughout the body. In the developing retina, the degradation of retinoic acid limits the formation of blue cones in the central region.
The second influence is thyroid hormone. Although thyroid hormones are best known for regulating metabolism, they also have important roles in growth and development. In the developing fovea, the hormone appears to encourage the remaining blue cones to transform into red and green cones.
“First, retinoic acid helps set the pattern. Second, thyroid hormone is responsible for transforming the remaining cells,” Johnston said. “This is very important because if you have blue cones there, your vision will be impaired.”
The findings concern how vitamin A signaling guides eye development before birth. They do not establish that taking vitamin A supplements can improve clear vision in adults.
A challenge to a decades-old theory
The results offer an alternative to a model that has shaped vision research for decades. Under the long-standing explanation, blue cones appear in the fovea and then move away as the retina develops. Scientists generally believed that once cone cells acquired a particular identity, that identity remained fixed.
The new findings suggest that at least some blue cones may not simply change location. Instead, they may change identity and become red or green cones as the eye develops.
“The leading model in this field about 30 years ago was that some blue cones that you get in that area somehow move out of the way, determine what these cells will become in the future, and remain this type of cell forever,” Johnston said. “We still can’t completely rule it out, but our data support a different model: These cells actually transform over time, which is really surprising.”
The researchers have not completely ruled out the possibility that some cells migrate. Even so, their observations support the idea that developing cells in the fovea are more flexible than previously recognized.
This possibility could change how scientists investigate the formation of human color vision and the development of the retina’s most specialized regions.
Could the findings help restore lost vision?
The study may help explain not only how healthy eyes develop but also how researchers might eventually treat diseases that damage the retina.
One potential application involves macular degeneration, a major cause of central vision loss, particularly among older people. The disease damages the macula, the part of the retina responsible for detailed central vision, and can seriously affect reading, driving and face recognition. Treatments can slow or manage the progression of some forms of the disease, but there is currently no cure.
Understanding how the retina produces specialized light-sensitive cells could eventually help scientists generate healthy replacement cells in the laboratory.
Johnston’s team is working to improve retinal organoids so they more closely reproduce the structure and function of the human eye. The long-term goal is to gain precise control over populations of photoreceptors, the cells that detect light, with the possibility of transplanting them into damaged retinas.
Study author Katarzyna Hussey, a former doctoral student in Johnston’s laboratory, said the approach could open new directions in vision restoration research. Hussey is now a molecular cell biologist at CiRC Biosciences, a cell therapy company in Chicago.
“The goal of using this organoid technology is to eventually create a nearly custom-tailored population of photoreceptors. A big possibility is cell replacement therapy, which introduces healthy cells that could reintegrate into the eye and potentially restore lost vision,” Hussey said.
The proposed treatment would introduce healthy cells that could integrate with existing retinal tissue and potentially replace functions lost to disease. Before that becomes possible, researchers will need to show that transplanted cells can survive, connect correctly with the eye’s existing circuitry and function safely.
Hussey emphasized that the technology is far from routine clinical use and still requires extensive development and testing.
“These are very long-term experiments, and of course we need to do some optimization for safety and efficacy studies before we move into the clinic. But it’s a viable journey.”
For now, the discovery provides a clearer explanation of how the human eye develops its ability to see fine details. By showing how vitamin A signaling and thyroid hormones help shape the retina, the researchers have advanced understanding of early vision development and identified possible directions for future efforts to restore sight after disease.
Source: www.sciencedaily.com
